In July of 2008, I will graduate as the first joint internal medicine and clinical genetics trainee in the country. This unique opportunity informs my vision of how I can integrate clinical and scientific work in a way that will advance patient care. I believe most disease has a hereditary basis, either as a result of highly penetrant alleles (autosomal dominant conditions) or weakly penetrant alleles (low-risk association alleles). In either case, the causative alleles are a window into the mechanisms underlying the pathophysiology and represent potential therapeutic targets. As a scientist, with a specific interest in diabetes, I will use this understanding to direct my research. As a clinician, I will staff a weekly endocrine genetics clinic. Over time, the clinic will increasingly be focused on low penetrance risk alleles which will be used to guide patient-specific preventive and therapeutic care. In the long-term, I hope to advance the treatment of diabetes through laboratory-based bench research and through insights garnered from direct patient care. This proposal describes a 5-year research program to acquire expertise in the fields of ( cell biology, islet ( cell physiology, and regenerative medicine. At present, the molecular mechanisms that are responsible for (-cell failure and (-cell regeneration remain obscure. This research plan is focused on characterizing the molecular mechanisms of (-cell replication, on identifying small-molecules that promote (-cell growth and on elucidating the basic physiology of (-cells. With a better understanding of the underlying mechanisms of (-cell regeneration, we will acquire insight into the basic pathophysiology of diabetes. Furthermore, this research program provides a platform for me to launch a career as an independent investigator. The studies proposed here will be carried out under the mentorship of Douglas Melton Ph.D., an accomplished investigator in the field of regenerative medicine with specific expertise in Diabetes. I will have regular meetings with collaborators and advisors to review my progress and to promote my career advancement I will also participate in scientific courses to broaden my knowledge and skills. Finally, the success of this proposal and of my career will be fostered by the extraordinary research environment created by the consortium of the Stem Cell and Regenerative Medicine Department and the BWH Genetics Division. PUBLIC HEALTH RELEVANCE: Diabetes and its related complications are a major global health care burden. At present, oral therapy is typically of limited value and intensive insulin therapy, even when performed by the most attentive patients, fails to avert most disease related pathology. This proposal is focused on harnessing the regenerative capacity of islet (-cells to prevent the onset and progression of disease.